Platelet-activating factor (PAF) has been associated with various biological activities and pathways, thus making it an important mediator responsible for a variety of physiological processes including, but not limited to, activation and aggregation of platelets, smooth muscle contraction, pathogenesis of immune complex deposition, inflammation, immunomodulation, respiratory, cardiovascular and intravascular alterations. These physiological processes are associated with a large group of diseases, such as, for example, cardiovascular disorders, asthma, lung edema, endotoxin shock, adult respiratory distress syndrome, and inflammatory diseases, autoimmunization and graft rejection.
U.S. Pat. No. 4,804,658 discloses a class of imidazopyridine derivatives useful in the treatment of diseases or disorders mediated by platelet-activating factor. The present invention is distinct from this disclosure in that in the present invention the benzamide moiety is attached to the nitrogen (position 5) which makes up the six membered ring of the imidazopyridine ring system as opposed to the disclosure wherein the benzamide moiety is attached to one of the nitrogens which makes up the five membered ring of the imidazopyridine ring system.
U.S. Pat. Nos. 4,914,108 and 5,019,581 disclose a class of imidazopyridine derivatives useful in the treatment of diseases or disorders mediated by Platelet-activating Factor. The present invention is distinct from those disclosures in that in the present invention the pyridine ring of the imidazopyridine ring system is substituted by a phenyl substituent which may be further substituted.
The present invention relates to a novel class of compounds represented by the formula ##STR2## or a pharmaceutically acceptable acid addition salt thereof, wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrido, straight or branched chain alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms;
R.sub.3 is a group substituted at one or more of the 2, 3, 5 or 6 positions of the phenyl ring, said group being independently selected from hydrido, alkyl having 1 to 6 carbon atoms, halogen, alkoxy having 1 to 6 carbon atoms and thioalkyl wherein the alkyl has 1 to 6 carbon atoms; and PA1 R.sub.4 is a group substituted at one or more of the 2, 3, 4, 5 or 6 positions of the phenyl ring, said group being independently selected from hydrido, alkyl having 1 to 6 carbon atoms, thioalkyl wherein the alkyl has 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms and fluoro.
The invention further relates to pharmaceutical compositions comprising a compound of formula I. Such compounds and compositions have potent and specific PAF antagonistic activities and are thereby useful in the treatment of various diseases or disorders mediated by PAF, for example inflammation, cardiovascular disorders, asthma, lung edema, and adult respiratory distress syndrome.
A preferred embodiment of the present invention is N-cyclohexyl-3-methoxy-N-(1-methylethyl)-4-[(4-phenyl-5H-imidazo4,5-c]pyri din-5-yl]methyl]benzamide which has the following structure ##STR3##
As used herein the term "alkyl having 1 to 6 carbon atoms": refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and isohexyl.
As used herein the term "cycloalkyl having 3 to 8 carbon atoms" includes cycloalkyl groups having from 3 to 8 carbons. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and 3,5-dimethylcyclohexyl.
As used herein the term halogen includes fluoro, chloro and bromo.
As used herein the term "alkoxy having 1 to 6 carbon atoms" refers to straight or branched chain ethers. Illustrative of such groups are methoxy, ethoxy, propoxy, butoxy and isopropoxy.
The term "thioalkyl" refers to straight or branched thio-containing radicals, respectively having alkyl portions of one to six attached.
Included within the embodiments of the present invention are the tautomeric forms of the described compounds, isomeric forms including geometric isomers, enantiomers and diastereoisomers, and the pharmaceutically acceptable salts thereof.
The term "pharmaceutically acceptable acid addition salt" refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human consumption. Examples of pharmacologically acceptable acid addition salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, and tartrate salts. All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid with the corresponding compound of Formula I.
This invention also relates to a method of treatment for patients (or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to PAF as previously described, and more specifically, a method of treatment involving the administration of compound (I) as the active ingredient.
Accordingly, compound (I) can be used among other things to reduce inflammation, to correct respiratory, cardiovascular, and intravascular alterations or disorders, and to regulate the activation or coagulation of platelets, the pathogenesis of immune complex deposition and smooth muscle contractions.
For the treatment of inflammation, cardiovascular disorder, asthma, or other diseases mediated by PAF, compound (I) may be administered orally, topically, parenterally, or by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitoneally.
The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art.
Accordingly, the invention provides a class of novel pharmaceutical compositions comprising one or more compounds of the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and if desired other active ingredients.
The dosage regimen for treating a condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the infection; the route of administration; and the particular compound employed and thus may vary widely.
Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (from about 0.5 mg to about 5 gs. per patient per day). Preferably, from about 0.01 mg to about 50 mg per kilogram of body weight per daily dosage produces highly effective results (about 0.5 mg to about 2.5 gm per patient per day).
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules which may be taken singlely or multiply. These may with advantage contain an amount of active ingredient from about 0.5 to 250 mg preferably from about 0.5 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.01 to 100 mg/kg body weight, particularly from about 0.01 to 75 mg/kg body weight may be appropriate.
The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. A suitable daily dose is from about 0.01 to 100 mg/kg body weight injected per day in single or multiple doses or continuous infusion depending on the disease being treated. A preferred daily dose would be from about 0.01 to 50 mg/kg body weight.
For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thus tableted or encapsulated for convenient administration. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The pharmaceutical compositions may be made up in a solid form such as granules, powders or suppositories or in a liquid form such as solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form which may be taken singlely or multiply will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 250 mg of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 0.5 mg to about 150 mg of active ingredient.
The compounds of Formula (I) may be prepared in accordance with the following Schemes A to C. ##STR4##